Original Article
Impaired Function of Macrophage Fcγ Receptors and Bacterial Infection in Alcoholic Cirrhosis
N Engl J Med 1994; 331:1122-1128October 27, 1994
- Abstract
Background
Bacterial infection is a frequent and often fatal complication in patients with cirrhosis. Macrophages play an important part in the host defense against infection because their Fcγ receptors recognize antibody-coated bacteria.
Methods
We prospectively studied macrophage Fcγ-receptor function in vivo and in vitro in 49 patients with alcoholic cirrhosis, 10 alcoholics without cirrhosis, and 20 normal volunteers.
Results
The clearance of IgG-sensitized autologous red cells was decreased in 37 of the 49 patients with cirrhosis but in none of the subjects without cirrhosis. In the 49 patients clearance was inhibited by a mean (±SE) of 47 ±3 percent at 1 hour and 53 ±3 percent at 1 1/2 hours, as compared with the clearance in the normal controls (P<0.001). The impairment of macrophage Fcγ-receptor-dependent clearance correlated with the degree of liver insufficiency but not with age, sex, nutritional status, HLA haplotype, or the presence of circulating immune complexes. The clearance of unsensitized and heat-altered autologous erythrocytes was normal. In vitro recognition of IgG-sensitized red cells by monocytes from the patients was not significantly decreased. During a two-year follow-up period, 11 patients had severe bacterial infections, and in 4 they were fatal. The mean clearance of IgG-sensitized red cells in these 11 patients (half-time, 126.2 ±22 hours) was significantly impaired, as compared with that in the 38 patients without severe infection (half-time, 32.2 ±18 hours, P<0.001).
Conclusions
The function of macrophage Fcγ receptors is impaired in patients with alcoholic cirrhosis, and this impairment probably contributes to the high incidence of bacterial infections among such patients.
Media in This Article
Figure 1
Macrophage Fcγ-Receptor-Mediated Clearance of IgG-Sensitized Radiolabeled Red Cells in 49 Patients with Alcoholic Cirrhosis, 10 Alcoholic Subjects without Cirrhosis, and 20 Normal Controls; Clearance of Unsensitized Autologous Red Cells in 5 Patients and 5 Controls; and Clearance of Heat-Damaged Red Cells in 5 Patients and 5 Controls.Figure 2
Macrophage Fcγ-Receptor-Mediated Clearance of IgG-Sensitized Radiolabeled Red Cells in 17 Patients with Mild Hepatic Insufficiency (Group 1), 17 Patients with Moderate Hepatic Insufficiency (Group 2), 15 Patients with Severe Hepatic Insufficiency (Group 3), and 20 Controls.Article Activity
- Article
Patients with cirrhosis have an increased incidence of bacterial infection1. Although immunologic abnormalities have been observed in such patients, the precise mechanisms responsible for the increased frequency of infection are uncertain. Macrophage Fcγ receptors are important in the host defense, since they participate in the clearance of IgG-coated microorganisms. We studied the clearance of IgG-sensitized cells by macrophage Fcγ receptors in patients with alcoholic cirrhosis, the most common type of cirrhosis2.
The functional integrity of Fcγ receptors has been widely studied in patients with autoimmune disease through measurement of the clearance of radiolabeled IgG-sensitized erythrocytes by splenic macrophages3,4. Macrophage Fcγ-receptor function has been observed to be decreased in patients with certain HLA haplotypes and in patients with such autoimmune disorders as systemic lupus erythematosus, Sjogren's syndrome, and dermatitis herpetiformis3,4. This finding has been attributed to the occupation of these receptors on the macrophages by immune complexes. We have previously observed that macrophage Fcγ-receptor function is impaired in patients with end-stage renal disease who are undergoing hemodialysis, and that this impairment probably contributes to the observed immunodepression and high prevalence of infection among such patients5.
Methods
Patients
We studied 49 consecutive patients in Spain (16 women and 33 men) whose mean (±SD) age was 55.2 ±8.3 years. All patients had alcoholic cirrhosis confirmed by biopsy and were followed for a minimum of two years. Ten alcoholic subjects without cirrhosis (4 women and 6 men; mean age, 45 ±7 years) and 20 healthy volunteers (6 women and 14 men; mean age, 52 ±12 years) served as concurrent controls. Patients who had undergone portosystemic shunting or liver transplantation, had active infection or acute hypovolemia, or were receiving immunosuppressant medications were excluded from the study. The patients were divided into three groups according to whether the degree of hepatic insufficiency was mild (group 1), moderate (group 2), or severe (group 3), according to established criteria6.
Study Protocol
All patients gave informed written consent, and the study was approved by the appropriate institutional review boards.
Blood samples were obtained from the patients and controls on admission for the following measurements: blood glucose and urea nitrogen, sodium, potassium, chloride, total calcium, phosphate, magnesium, creatinine, uric acid, total cholesterol, triglycerides, cholesterol (high- and low-density lipoprotein), serum aspartate and alanine aminotransferases, γ-glutamyltransferase, 5'-nucleotidase, alkaline phosphatase, serum protein electrophoresis, complete blood count, prothrombin time, activated partial-thromboplastin time, fibrinogen, and alpha-fetoprotein. Serum IgG, IgA, and IgM concentrations were determined by radial immunodiffusion (Behring Diagnostics, Madrid). Serum C4 concentrations were determined by hemolytic titration,7 and serum C3 and C3a des-arginine concentrations by radial immunodiffusion (Behring Diagnostics). Plasma zinc levels were measured by absorption spectrophotometry (Pye Unicam SP 190). Circulating immune complexes were determined by 125I-labeled C1q binding8. A peripheral-smear examination was performed after Wright-Giemsa staining to detect the presence of Howell-Jolly bodies, an index of splenic function9 (negative in all patients). Macrophage Fcγ-receptor-dependent clearance was determined in vivo, and Fcγ-receptor-mediated recognition of IgG-sensitized cells by blood monocytes in vitro. Abdominal ultrasonography was performed to detect splenomegaly,9 which was present in 27 of the 49 patients and in none of the controls. The study protocol was the same for the patients and the controls. The results of all the above studies were normal in the 10 alcoholic subjects without cirrhosis, except for the mean corpuscular volume.
Preparation of Human IgG Anti-RhD Antibodies
Human IgG anti-RhD antibodies were prepared from serum from a single donor by ammonium sulfate precipitation followed by Sephacryl S-300 gel filtration and quartenary aminoethyl ion-exchange chromatography (Pharmacia, Madrid). No IgM was detected by double immunodiffusion (Ouchterlony analysis3). The final IgG fraction was passed through a Millipore filter and tested for pyrogenicity and sterility. The final IgG fraction was negative for human immunodeficiency virus type 1 (HIV-1) by the enzyme-linked immunosorbent assay (Pasteur Institute, Madrid), the Western blot technique (Pasteur Institute), and the quantitative end-point dilution method10. The number of IgG (anti-RhD) molecules per red cell was determined as previously described with 125I-labeled anti-IgG antibodies11. Clearance studies were performed with erythrocytes sensitized so that approximately 600 molecules of IgG were present on each red cell. When Fcγ-receptor-dependent recognition by blood monocytes was studied in vitro, each red cell was coated with 400, 800, or 1600 molecules of IgG.
Macrophage Fcγ-Receptor-Mediated Clearance
Clearance studies were performed as previously described5,12,13. In brief, erythrocytes (RhD-positive) were isolated from all subjects, washed three times in physiologic saline, spectrophotometrically standardized to a concentration of 6.6 × 108 cells per milliliter, and radiolabeled with 51Cr (potassium dichromate, Amersham, Buckinghamshire, United Kingdom). An aliquot of cells was sensitized by adding to it drop by drop an appropriate dilution of purified human IgG anti-RhD antibodies. The mixture was incubated at 37 °C for 30 minutes, and the sensitized 51Cr-labeled erythrocytes were washed four times in saline and resuspended to a concentration of 3.3 × 106 cells per milliliter in Hanks' balanced salt solution (M.A. Bioproducts, Madrid). An aliquot of cells (10 ±0.3 ml with 2.5 micro Ci of radioactivity) was injected through an antecubital vein, and the survival of red cells was determined in serial blood samples obtained over a period of 48 hours. Neither the specific activity of the radiolabeled erythrocytes nor the volume injected differed significantly between the patients and the controls.
Clearance curves were plotted by expressing the number of counts per minute at each point in time as a percentage of the number of counts at 10 minutes, the zero point. The time required for the clearance of 50 percent of the IgG-coated red cells (the half-time) was calculated and then correlated with the clinical and serologic data. In addition, to determine the clearance on each day, the percentage of inhibition of clearance above the control value was calculated at 1, 1 1/2, 2, 8, 24, and 48 hours, according to the formula
% inhibition = 100 × 1 - ((CPMb-CPMx) / (CPMb-CPMc)),
where CPMb denotes the number of counts per minute in a control subject who received an injection of unsensitized autologous red cells, CPMx the number of counts in a patient who received IgG-coated (sensitized) autologous red cells, and CPMc the number of counts in a control subject who received autologous IgG-sensitized red cells. Controls with body weights comparable to those of the patients were studied simultaneously with them, and the counts per minute at the zero point (10 minutes) were similar. By means of the above formula, patients could be compared with controls studied on the same day, and the results could be expressed as the percentage of the change in clearance; thus, 100 percent inhibition of clearance indicated that clearance in a patient who received IgG-coated red cells was identical to that in a control who received unsensitized red cells5,14. Serum C3, C3a des-arginine, and C4 concentrations were measured to assess complement activation during the clearance of IgG-coated red cells. No marked complement activation was observed in any of the patients.
In three subgroups (five patients with alcoholic cirrhosis, five alcoholic subjects without cirrhosis, and five controls) we examined the clearance of autologous 51Cr-labeled but unsensitized red cells and the clearance of 51Cr-labeled heat-damaged (i.e., heated for 30 minutes at 56 °C) autologous red cells.
Monocyte Recognition of IgG-Coated Cells
The recognition of IgG-coated red cells by isolated blood monocytes was determined as previously described15,16. In brief, confluent monolayers of 5.5 × 105 monocytes were obtained from defibrinated blood after density-gradient centrifugation (Ficoll-Isopaque) and plastic adherence to petri dishes (Nunc, Amsterdam). An aliquot of 2 × 107 51Cr-labeled, IgG-coated red cells was added to each monocyte monolayer. The petri dishes were then incubated at 37 °C in 5 percent carbon dioxide for 45 minutes, washed to detach unbound red cells, and treated with 0.086 M EDTA solution to remove adherent monocytes and monocyte-bound IgG(anti-RhD)-sensitized red cells. The treatment with EDTA removed all adherent monocytes and all radioactivity. The percentage of 51Cr-labeled and IgG-sensitized red cells recognized by peripheral-blood monocytes was determined according to the formula
% of red cells bound to monocyte monolayers = ((cpm for IgG(anti-RhD)-coated red cells removed with EDTA)/(cpm for IgG(anti-RhD)-coated red cells added to monocyte)) × 100.
No phagocytosis of anti-RhD-sensitized erythrocytes by peripheral-blood monocytes occurs under these experimental conditions15,16.
Igg2b-antibody-sensitized sheep erythrocytes were also prepared as previously described17. In brief, 1 × 109 sheep red cells in 1.0 ml of 0.01 M EDTA buffer were sensitized by adding mouse anti-sheep red-cell monoclonal antibody Sp2/HL, subclass IgG2b (Serotec, Bicester, United Kingdom), in 0.1 ml at 37 °C for one hour. The final antibody dilutions used to prepare these cells were between 1:10 and 1:80. The IgG-sensitized sheep red cells were washed twice and resuspended in Hanks' balanced salt solution to a final concentration of 1 × 108 cells per milliliter.
Monocyte recognition of rabbit IgG-sensitized red cells in vitro was assessed as previously reported17,18. In brief, 1 × 108 IgG-coated red cells or unsensitized control red cells were added to monocyte monolayers containing 1 × 106 cells. These cells were incubated at 4 °C or 37 °C in phosphate buffer at an ionic strength of micro = 0.07 or micro = 0.15, respectively. After two hours, the plates were washed and stained with Wright-Giemsa. Two hundred monocytes were counted under light microscopy in a blinded fashion to assess the number of IgG-sensitized red cells bound to each monocyte. Monocytes binding more than 3 red cells per monocyte were determined. These experiments were performed in five patients from each group of subjects with alcoholic cirrhosis (groups 1, 2, and 3), eight alcoholic subjects without cirrhosis, and eight normal volunteers.
The studies were repeated in both patients and controls. Both the clearance studies and the in vitro studies with blood monocytes were repeated six months after the original studies in nine of the patients with cirrhosis in whom severe infection had developed, in six of the patients with cirrhosis who did not have a history of infectious complications, in six of the alcoholic subjects without cirrhosis, and in six normal volunteers. In each subject the results of the repeated studies were the same as those of the original studies.
HLA Typing
HLA typing was performed by the tissue-typing laboratory of the Virgen del Rocio University Hospital in Seville, Spain.
Assessment of Nutritional Status
Nutritional status was evaluated according to anthropometric, biochemical, and immunologic measurements19-22. Dry body weight, relative body weight, and the percentage of ideal body weight were also determined. The anthropometric data were compared with standard values for the local population23. Serum albumin and transferrin were measured to evaluate the serum protein level. Malnutrition was classified, according to previously established criteria,19-24 as marasmus, kwashiorkor, or a mixed type. All malnourished patients had malnutrition of the mixed type. There was a high incidence of protein-calorie malnutrition of the mixed type (in 17 of the 49 patients [35 percent]). The total body weight did not change.
Cutaneous hypersensitivity responses to standard concentrations of four antigens -- purified protein derivative, Trycophyton rubrum, Candida albicans, and streptokinase-streptodornase -- were used to evaluate cell-mediated immunity, as previously described20,25. A response was considered positive when the diameter of induration was more than 5 mm. A normal response was indicated by positive responses to three or four antigens, an abnormally low response by a positive response to one or two antigens, and anergy by negative responses to all four antigens.
Statistical Analysis
The in vivo clearance curves at the designated times were analyzed with Student's t-test to calculate P values for the differences between the controls and the patients. The in vitro Fcγ-receptor-dependent recognition of red cells by monocytes and the clearances in patients and controls were assessed with the Wilcoxon rank-sum test for unpaired data. The relation of the clearance rate (half-time) or monocyte Fcγ-receptor-dependent recognition of IgG-coated red cells in vitro to the results of serologic tests was analyzed with the Spearman rank-correlation test. The data are presented as means ±SE.
Results
Clearance studies were performed in the 49 patients with alcoholic cirrhosis who met the criteria for inclusion in the study. The results demonstrated that the clearance of IgG-coated red cells by macrophage Fcγ receptors was significantly impaired (P<0.001) (Figure 1Figure 1
Macrophage Fcγ-Receptor-Mediated Clearance of IgG-Sensitized Radiolabeled Red Cells in 49 Patients with Alcoholic Cirrhosis, 10 Alcoholic Subjects without Cirrhosis, and 20 Normal Controls; Clearance of Unsensitized Autologous Red Cells in 5 Patients and 5 Controls; and Clearance of Heat-Damaged Red Cells in 5 Patients and 5 Controls.). At 1 and 1 1/2 hours, clearance was inhibited by 47 ±3 and 53 ±3 percent, respectively, as compared with the clearance in the normal volunteers and the alcoholic subjects without cirrhosis. Clearance was inhibited by 15 to 83 percent in 37 patients and by 5 to 12 percent in 6. In contrast, the clearance of unsensitized and heat-damaged red cells in the patients did not differ from that in the alcoholic subjects without cirrhosis and the healthy volunteers (Figure 1).The patients with cirrhosis were classified according to the degree of hepatic insufficiency. Clearance studies in these three groups of patients are presented in Figure 2Figure 2
Macrophage Fcγ-Receptor-Mediated Clearance of IgG-Sensitized Radiolabeled Red Cells in 17 Patients with Mild Hepatic Insufficiency (Group 1), 17 Patients with Moderate Hepatic Insufficiency (Group 2), 15 Patients with Severe Hepatic Insufficiency (Group 3), and 20 Controls.. The clearance of IgG-coated red cells was significantly impaired (P<0.001) in the patients with moderate (group 2) or severe (group 3) hepatic insufficiency. At 1 and 1 1/2 hours, the mean inhibition of macrophage Fcγ-receptor-mediated clearance was 47 ±3 and 66 ±4 percent, respectively, for group 2 and 59 ±5 and 81 ±6 percent, respectively, for group 3. At 1 and 1 1/2 hours, Fcγ-receptor-mediated clearance of IgG-coated red cells was impaired in the patients with mild hepatic insufficiency (group 1), but the difference was not significant.Patients were followed for at least two years after the clearance studies. Six patients died: two of massive hemorrhage from ruptured esophageal or gastric varices (in the 15th and 17th months of follow-up), two of spontaneous bacterial peritonitis with Escherichia coli (in the 14th and 20th months of follow-up), and two of gram-negative sepsis due to E. coli and Serratia marcescens (in the 16th and 21st months of follow-up). Eleven patients had severe infection: five had spontaneous bacterial peritonitis (E. coli), and six had sepsis (due to E. coli in three, Staphylococcus aureus in one, Pseudomonas aeruginosa in one, and S. marcescens in one). When the clearance of IgG-coated red cells in the patients with severe infection was compared with the clearance in the patients without infection, those with infection were found to have a significantly longer half-time (126.2 ±22 vs. 32.2 ±18 hours, P<0.001) (Figure 3Figure 3
Macrophage Fcγ-Receptor-Mediated Clearance of IgG-Coated Red Cells (Half-Time) in 49 Patients with Alcoholic Cirrhosis and 20 Controls.) in the clearance studies performed at the time of their enrollment in the study. Of the 11 patients with half-times of 100 hours or more, 10 later had severe bacterial infections. In contrast, of the 38 patients with half-times under 100 hours, only 1 had a severe bacterial infection. Thus, a defect in macrophage Fcγ-receptor-mediated clearance identified patients in whom severe infection subsequently developed.We analyzed the clearance (half-time) of IgG-coated red cells in relation to several indications of liver impairment (abnormal values for serum aspartate and alanine aminotransferases, γ-glutamyltransferase, 5'-nucleotidase, bilirubin [total, direct, and indirect], prothrombin time, activated partial-thromboplastin time, fibrinogen, and serum albumin). None of these values, or the presence of splenomegaly, correlated with the extent of impairment of clearance of IgG-coated red cells.
Seven patients had elevated levels of circulating immune complexes. The clearance of IgG-coated red cells in these patients did not differ from that observed in the other 42 patients (data not shown). Furthermore, there was no correlation between the level of circulating immune complexes and the extent of impairment of the recognition of IgG-coated red cells by monocytes (see below).
We also studied peripheral-blood monocytes from our patients (Figure 4Figure 4
Recognition of Human IgG (Anti-RhD)-Coated Red Cells by Monocytes from 49 Patients with Alcoholic Cirrhosis, 10 Alcoholic Subjects without Cirrhosis, and 20 Normal Controls.). Erythrocytes from a single RhD-positive donor were sensitized with three different concentrations of IgG anti-RhD antibodies. Monocytes isolated from the patients bound fewer IgG-coated red cells than did those from the controls, but the differences were not significant. There was no correlation between the extent of binding by monocytes and the degree of impairment of clearance. No differences were observed between the monocytes from patients in whom severe infection developed and those from patients without severe infection. Similarly, peripheral-blood monocytes isolated from the patients with cirrhosis did not bind significantly fewer IgG2b-sensitized red cells than monocytes from the alcoholic subjects without cirrhosis or those from the normal volunteers (Figure 5Figure 5
Recognition of Mouse IgG2b-Coated Red Cells by Monocytes from 49 Patients with Alcoholic Cirrhosis, 10 Alcoholic Subjects without Cirrhosis, and 20 Normal Controls.).Neither the clearance of IgG-sensitized red cells nor the in vitro recognition of IgG-coated red cells by monocytes from the patients correlated with sex, age, time elapsed since the diagnosis of alcoholic cirrhosis, or any of the serologic measurements, including the immunoglobulin level. Furthermore, there was no relation between the clearance of IgG-coated red cells or their recognition in vitro by monocytes and the HLA haplotype or the nutritional status of the patients.
The plasma zinc level was 120 ±4.6 μg per deciliter (18.4 ±0.7 μmol per liter) in the healthy volunteers and 83.3 ±3.7 μg per deciliter (12.7 ±1.3 μmol per liter) in the patients with alcoholic cirrhosis (P<0.001). However, there was no correlation between the plasma zinc level and the degree of impairment of clearance in vivo or the recognition of IgG-coated red cells by monocytes in vitro. Similarly, malnutrition was not associated with impairment of the clearance rate or with in vitro recognition of IgG-sensitized red cells by monocytes. Neither the macrophage Fcγ-receptor-mediated clearance nor the binding by monocytes of IgG anti-RhD antibodies or IgG2b-coated red cells correlated with the nutritional status of the patients, as indicated by anthropometric, biochemical, and immunologic values.
Discussion
Infection is a major cause of morbidity and mortality in patients with cirrhosis1,26-28. Cirrhosis is primarily due to consumption of alcohol,2 and the incidence of infectious complications among hospitalized patients with alcoholic cirrhosis is very high. In several studies 30 to 50 percent of patients presented with bacterial infection on admission or infection developed during their hospital stay -- an incidence far in excess of that reported for the general hospital population1. Most bacterial infections in patients with cirrhosis are acquired in the hospital, with nosocomial infections developing in 20 to 35 percent of patients -- again, an incidence far above that in the general hospital population1. In our study, severe infection developed in 11 of 49 patients over a two-year period, with fatal complications in 4.
We observed that the clearance of IgG-coated red cells is impaired in patients with alcoholic cirrhosis. Since this clearance is mediated by splenic macrophage Fcγ receptors,5,12-14,29-31 our data indicate that splenic macrophage Fcγ-receptor function is impaired in such patients. This abnormality was found in the majority of patients (43 of 49), particularly in those with advanced liver insufficiency (Figure 2), as assessed by an established clinical-staging protocol6. Furthermore, impairment of splenic macrophage Fcγ-receptor function predisposes such patients to bacterial infection. The patients in whom severe infections subsequently developed had the most marked abnormalities of splenic macrophage Fcγ-receptor-dependent clearance (Figure 3).
Macrophage Fcγ-receptor-dependent clearance was previously examined in two29 and five30 patients with alcoholic cirrhosis. The extent of disease in these seven patients was comparable to that in our patients in group 1. Like our patients in group 1, the seven patients had no evidence of defective macrophage Fcγ-receptor-dependent clearance. In a study of patients with another cirrhotic disorder, primary biliary cirrhosis, a related defect, an abnormality in C3b-receptor-dependent clearance, was observed29. The relation of this receptor abnormality to infection in the patients was not studied.
Patients with systemic lupus erythematosus also have defective macrophage Fcγ-receptor-dependent clearance, and this defect correlates with the level of circulating immune complexes12,31. We observed defective macrophage Fcγ-receptor function in our patients with alcoholic cirrhosis in the absence of circulating immune complexes. Patients with systemic lupus erythematosus have an increased incidence of infection32. However, to our knowledge, there has not been a systematic study of the incidence of infection in relation to the defect in Fcγ-receptor-dependent clearance in such patients.
Splenomegaly has been associated with alterations in the clearance of radiolabeled particulate material by the reticuloendothelial system1. Like other investigators,29,30 however, we found no correlation between the clearance of IgG-coated or heat-damaged red cells and the presence of splenomegaly. Low plasma zinc levels and protein-calorie malnutrition have been associated with immunodepression in cirrhosis1,33. However, we found no relation between plasma zinc levels or malnutrition and the alteration of Fcγ receptors in our patients either in vivo or in vitro. Abnormalities in the expression or function of Fcγ receptors have been observed in association with certain HLA haplotypes3,12,31. In our study there was no correlation between the HLA haplotype and either macrophage Fcγ-receptor-dependent clearance or the recognition of IgG-coated cells by monocytes. Similarly, defective Fcγ-receptor-dependent clearance has been observed in patients with the acquired immunodeficiency syndrome (AIDS),34 but none of our patients had antibodies to HIV or any evidence of diseases related to AIDS.
Several predisposing factors have been proposed in the development of bacterial infection in patients with cirrhosis. Significantly increased numbers of gram-negative bacilli have been reported in the jejunal flora of patients with cirrhosis35. Several in vitro and in vivo studies have demonstrated a reduction of cell-mediated immunity,36,37 as well as reduced metabolic activity and neutrophil phagocytic and killing capacity38. Reduced serum39 and ascitic-fluid40,41 opsonic activity has been noted1. In addition, patients with cirrhosis frequently have malnutrition24,36 or acute hypovolemia, which may exacerbate the dysfunction of the reticuloendothelial system1,33,42.
Previous studies of macrophage function in cirrhosis have focused on the rate of clearance of radiolabeled colloid or microaggregated human serum albumin1,39,43. Abnormalities in hepatic circulation have been reported in association with increased intrahepatic shunting, and such abnormalities may contribute to this nonspecific clearance44. Such studies demonstrating an alteration in reticuloendothelial-system clearance did not assess macrophage Fcγ-receptor function. Infection with pyogenic organisms is very common in patients with cirrhosis, and the Fcγ receptors probably have a critical role in the specific clearance of IgG-coated microorganisms, as part of the host defense against bacterial infection5.
We further explored the Fcγ-receptor abnormality in our patients. Since tissue macrophages from our patients were unavailable for study, we examined their peripheral-blood monocytes, which are related to tissue macrophages. The peripheral-blood monocytes bound normal amounts of the same human IgG-coated red cells whose clearance was impaired in vivo. Monocytes express two Fcγ-receptor proteins, FcγRI and FcγRII45,46. Data from our laboratory indicate that the recognition of IgG anti-RhD-coated erythrocytes by monocytes is mediated primarily by FcγRI47. Thus, the binding of IgG-coated cells by monocyte FcγRI is not intrinsically defective in patients with alcoholic cirrhosis. The in vitro binding of mouse IgG2b-coated erythrocytes by human peripheral-blood monocytes has been shown to be mediated primarily by the monocyte receptor FcγRII17,47. Our results demonstrate that monocytes from patients with alcoholic cirrhosis bind normal amounts of IgG2b-coated red cells. Thus, the binding of IgG-coated cells by monocyte FcγRII is also not defective in such patients.
In addition to FcγRI and FcγRII, tissue macrophages express a third Fcγ-receptor protein, FcγRIII45,46. The alteration in the clearance of IgG-coated cells by splenic macrophage Fcγ receptors, which predisposes patients with alcoholic cirrhosis to severe bacterial infection, may be accounted for by an abnormality in this third class of Fcγ receptors. We have previously reported that patients with end-stage renal disease have a defect in splenic macrophage Fcγ-receptor-dependent clearance that correlates with the incidence of severe infection5. Studies of blood monocytes from these patients with renal failure suggested that FcγRI was not responsible for the alteration in clearance5. Thus, the results of studies in patients with chronic renal disease are similar to those in patients with alcoholic cirrhosis, indicating the presence of a macrophage Fcγ-receptor defect that predisposes these patients to severe bacterial infection.
Supported by grants from the National Institutes of Health (AI/HL-22193) and the Ministerio de Educacion y Ciencia (PM92-0259 and RE90-28515062).
We are indebted to Ruth Rowan and Jeanne Venney for their assistance in preparing the manuscript.
Source Information
From the Department of Medicine, Hospital of the University of Cadiz, Puerto Real, Spain (F.G., P.R.), and the University of Pennsylvania School of Medicine, Philadelphia (A.D.S.).
Address reprint requests to Dr. Schreiber at the University of Pennsylvania School of Medicine, 7 Silverstein Bldg., 3400 Spruce St., Philadelphia, PA 19104.
- References
References
1
Rimola A. Infections in liver disease. In: McIntyre N, Benhamou J-P, Bircher J, Rizzetto M, Rodes J, eds. Oxford textbook of clinical hepatology. Vol. 2. Oxford, England: Oxford University Press, 1991:1272-84.
2
Deaths and hospitalizations from chronic liver disease and cirrhosis -- United States, 1980-1989
Medline3
Frank MM ,Lawley TJ ,Hamburger MI ,Brown EJ . Immunoglobulin G Fc receptor-mediated clearance in autoimmune diseases. Ann Intern Med 1983;98:206-218
Web of Science | Medline4
Kimberly RP ,Ralph P . Endocytosis by the mononuclear phagocyte system and autoimmune disease. Am J Med 1983;74:481-493
CrossRef | Web of Science | Medline5
Ruiz P ,Gomez F ,Schreiber AD . Impaired function of macrophage Fcγ receptors in end-stage renal disease. N Engl J Med 1990;322:717-722
Full Text | Web of Science | Medline6
Orrego H ,Kalant H ,Israel Y , et al. Effect of short-term therapy with propylthiouracil in patients with alcoholic liver disease. Gastroenterology 1979;76:105-115
Web of Science | Medline7
Gaither TA ,Alling DW ,Frank MM . A new one-step method for the functional assay of the fourth component (C4) of human and guinea pig complement. J Immunol 1974;113:574-583
Web of Science | Medline8
Zubler RH, Lamber P-H. The 125I-C1q binding test for the detection of soluble immune complexes. In: Bloom BR, David JR, eds. In vitro methods in cell-mediated and tumor immunity. New York: Academic Press, 1976:565-72.
9
Boyko WJ ,Pratt R ,Wass H . Functional hyposplenism: a diagnostic clue in amyloidosis: report of six cases. Am J Clin Pathol 1982;77:745-748
Web of Science | Medline10
Ho DD ,Moudgil T ,Alam M . Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med 1989;321:1621-1625
Full Text | Web of Science | Medline11
Cines DB ,Schreiber AD . Immune thrombocytopenia: use of a Coombs antiglobulin test to detect IgG and C3 on platelets. N Engl J Med 1979;300:106-111
Full Text | Web of Science | Medline12
Frank MM ,Hamburger MI ,Lawley TJ ,Kimberly RP ,Plotz PH . Defective reticuloendothelial system Fc-receptor function in systemic lupus erythematosus. N Engl J Med 1979;300:518-523
Full Text | Web of Science | Medline13
Schreiber AD ,Frank MM . Role of antibody and complement in the immune clearance and destruction of erythrocytes. I. In vivo effects of IgG and IgM complement-fixing sites. J Clin Invest 1972;51:575-582
CrossRef | Web of Science | Medline14
Friedman D ,Netti F ,Schreiber AD . Effect of estradiol and steroid analogues on the clearance of immunoglobulin G-coated erythrocytes. J Clin Invest 1985;75:162-167
CrossRef | Web of Science | Medline15
Gomez F ,Kelley M ,Rossman MD ,Dauber J ,Schreiber AD . Macrophage recognition of complement-coated lymphoblastoid cells. J Reticuloendothel Soc 1982;31:241-249
Medline16
Schreiber AD ,Parsons J ,McDermott P ,Cooper RA . Effect of corticosteroids on the human monocyte IgG and complement receptors. J Clin Invest 1975;56:1189-1197
CrossRef | Web of Science | Medline17
Rossman MD ,Ruiz P ,Comber P ,Gomez F ,Rottem M ,Schreiber AD . Modulation of macrophage Fcγ receptors by rGM-CSF. Exp Hematol 1993;21:177-183
Web of Science | Medline18
Schreiber AD ,Chien P ,Tomaski A ,Cines DB . Effect of danazol in immune thrombocytopenic purpura. N Engl J Med 1987;316:503-508
Full Text | Web of Science | Medline19
Blumenkrantz MJ ,Kopple JD ,Gutman RA , et al. Methods for assessing nutritional status of patients with renal failure. Am J Clin Nutr 1980;33:1567-1585
Web of Science | Medline20
Harvey KB ,Blumenkrantz MJ ,Levine SE ,Blackburn GL . Nutritional assessment and treatment of chronic renal failure. Am J Clin Nutr 1980;33:1586-1597
Web of Science | Medline21
Jelliffe DB. The assessment of the nutritional status of the community. World Health Organization monograph series no. 53. Geneva: World Health Organization, 1966.
22
Bistrian BR ,Blackburn GL ,Vitale J ,Cochran D ,Naylor J . Prevalence of malnutrition in general medical patients. JAMA 1976;235:1567-1570
CrossRef | Web of Science | Medline23
Jaurrieta Mas E . Valoracion del estado nutricion en clinica. Med Clin (Barc) 1983;81:584-588
Medline24
O'Keefe SJ ,El-Zayadi AR ,Carraher TE ,Davis M ,Williams R . Malnutrition and immunoincompetence in patients with liver disease. Lancet 1980;2:615-617
CrossRef | Web of Science | Medline25
Blackburn GL ,Bistrian BR ,Maini BS ,Schlamm HT ,Smith MF . Nutritional and metabolic assessment of the hospitalized patient. JPEN J Parenter Enteral Nutr 1977;1:11-22
CrossRef | Medline26
Almdal TP ,Skinhoj P . Spontaneous bacterial peritonitis in cirrhosis: incidence, diagnosis, and prognosis. Scand J Gastroenterol 1987;22:295-300
CrossRef | Web of Science | Medline27
Graudal N ,Milman N ,Kirkegaard E ,Korner B ,Thomsen AC . Bacteremia in cirrhosis of the liver. Liver 1986;6:297-301
Medline28
Almdal T ,Skinhoj P ,Friis H . Bacteremia in patients suffering from cirrhosis. Infection 1986;14:68-70
CrossRef | Web of Science | Medline29
Ekdahl KN ,Loof L ,Nyberg A ,Nilsson UR ,Nilsson B . Defective Fc receptor-mediated clearance in patients with primary biliary cirrhosis. Gastroenterology 1991;101:1076-1082
Web of Science | Medline30
Jaffe CJ ,Vierling JM ,Jones EA ,Lawley TJ ,Frank MM . Receptor specific clearance by the reticuloendothelial system in chronic liver diseases: demonstration of defective C3b-specific clearance in primary biliary cirrhosis. J Clin Invest 1978;62:1069-1077
CrossRef | Web of Science | Medline31
Parris TM ,Kimberly RP ,Inman RD ,McDougal JS ,Gibofsky A ,Christian CL . Defective Fc receptor-mediated function of the mononuclear phagocyte system in lupus nephritis. Ann Intern Med 1982;97:526-532
Web of Science | Medline32
Klinman DM, Steinberg AD. Systemic lupus erythematosus and overlap syndromes. In: Samter M, ed. Immunological diseases. Vol. 2. 4th ed. Boston: Little, Brown, 1988:1335-63.
33
Zetterman RK ,Sorrell MF . Immunologic aspects of alcoholic liver disease. Gastroenterology 1981;81:616-624
Web of Science | Medline34
Bender BS ,Frank MM ,Lawley TJ ,Smith WJ ,Brickman CM ,Quinn TC . Defective reticuloendothelial system Fc-receptor function in patients with acquired immunodeficiency syndrome. J Infect Dis 1985;152:409-412
CrossRef | Web of Science | Medline35
Drasor BS. The host and his gut flora: bacteria. In: Manuel PD, Walker-Smith JA, Tomkins A, eds. Infections of the gastrointestinal tract. Edinburgh, Scotland: Churchill Livingstone, 1986:1-9.
36
Morgan MY, McIntyre N. Nutritional aspects of liver disease. In: Wright R, Millward-Sadler GH, Alberti KGMM, Karran S, eds. Liver and biliary disease: pathophysiology, diagnosis, management. 2nd ed. London: Bailliere Tindall, 1985:119-60.
37
Hsu CCS ,Leevy CM . Inhibition of PHA-stimulated lymphocyte transformation by plasma from patients with advanced alcoholic cirrhosis. Clin Exp Immunol 1971;8:749-760
Web of Science | Medline38
Rajkovic IA ,Williams R . Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Hepatology 1986;6:252-262
CrossRef | Web of Science | Medline39
Rajkovic IA ,Williams R . Mechanisms of abnormalities in host defences against bacterial infection in liver disease. Clin Sci 1985;68:247-253
Web of Science | Medline40
Runyon BA . Patients with deficient ascitic fluid opsonic activity are predisposed to spontaneous bacterial peritonitis. Hepatology 1988;8:632-635[Erratum, Hepatology 1988;8:1184.]
CrossRef | Web of Science | Medline41
Tito L ,Rimola A ,Gines P ,Llach J ,Arroyo V ,Rodes J . Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors. Hepatology 1988;8:27-31
CrossRef | Web of Science | Medline42
Wallaert B ,Aerts C ,Colombel JF ,Voisin C . Human alveolar macrophage antibacterial activity in the alcoholic lung. Am Rev Respir Dis 1991;144:278-283
CrossRef | Web of Science | Medline43
Rimola A ,Soto R ,Bory F ,Arroyo V ,Piera C ,Rodes J . Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis. Hepatology 1984;4:53-58
CrossRef | Web of Science | Medline44
Huet PM ,Goresky CA ,Villeneuve JP ,Marleau D ,Lough JO . Assessment of liver microcirculation in human cirrhosis. J Clin Invest 1982;70:1234-1244
CrossRef | Web of Science | Medline45
Ravetch JV ,Kinet J-P . Fc receptors. Annu Rev Immunol 1991;9:457-492
CrossRef | Web of Science | Medline46
Unkeless JC . Function and heterogeneity of human Fc receptors for immunoglobulin G. J Clin Invest 1989;83:355-361
CrossRef | Web of Science | Medline47
Gomez F ,Chien P ,King M , et al. Monocyte Fcγ receptor recognition of cell-bound and aggregated IgG. Blood 1989;74:1058-1065
Web of Science | Medline
- Citing Articles (44)
Citing Articles
1
D. F. Florescu, A. M. McCartney, F. Qiu, A. N. Langnas, J. Botha, D. F. Mercer, W. Grant, A. C. Kalil. (2011) Staphylococcus aureus infections after liver transplantation. Infection
CrossRef2
Alexander R. Bonnel, Chalermrat Bunchorntavakul, K. Rajender Reddy. (2011) Immune Dysfunction and Infections in Patients With Cirrhosis. Clinical Gastroenterology and Hepatology 9:9, 727-738
CrossRef3
T. Bruns, J. Peter, S. Hagel, A. Herrmann, A. Stallmach. (2011) The augmented neutrophil respiratory burst in response to Escherichia coli is reduced in liver cirrhosis during infection§. Clinical & Experimental Immunology 164:3, 346-356
CrossRef4
A.P. Mitterhofer, F. Tinti, M. Mordenti, V. Pietropaolo, M. Colosimo, S. Ginanni Corradini, F. Chiarini, M. Rossi, G. Ferretti, F. Brunini, L. Poli, P.B. Berloco, G. Taliani. (2011) Polyomavirus BK Replication in Liver Transplant Candidates with Normal Renal Function. Transplantation Proceedings 43:4, 1142-1144
CrossRef5
Pedro Pimentel-Nunes, Roberto Roncon-Albuquerque, Nádia Gonçalves, Cátia Fernandes-Cerqueira, Hélder Cardoso, Rui Pedro Bastos, Margarida Marques, Cristina Marques, José Alexandre Sarmento, Carlos Costa-Santos, Guilherme Macedo, Manuel Pestana, Mário Dinis-Ribeiro, Adelino F. Leite-Moreira. (2010) Attenuation of toll-like receptor 2-mediated innate immune response in patients with alcoholic chronic liver disease. Liver International 30:7, 1003-1011
CrossRef6
Adam G. Testro, Paul J. Gow, Peter W. Angus, Sarah Wongseelashote, Narelle Skinner, Vesna Markovska, Kumar Visvanathan. (2010) Effects of antibiotics on expression and function of Toll-like receptors 2 and 4 on mononuclear cells in patients with advanced cirrhosis. Journal of Hepatology 52:2, 199-205
CrossRef7
Seon-Sook Han, Jae-Joon Yim, Chul-Gyu Yoo, Young Whan Kim, Sung Koo Han, Young-Soo Shim, Sang-Min Lee. (2010) Clinical Characteristics and Risk Factors for Nosocomial Candidemia in Medical Intensive Care Units: Experience in a Single Hospital in Korea for 6.6 Years. Journal of Korean Medical Science 25:5, 671
CrossRef8
Jan Petrasek, Pranoti Mandrekar, Gyongyi Szabo. (2010) Toll-Like Receptors in the Pathogenesis of Alcoholic Liver Disease. Gastroenterology Research and Practice 2010, 1-12
CrossRef9
Bettina Leber, Ursula Mayrhauser, Michael Rybczynski, Vanessa Stadlbauer. (2009) Störungen des angeborenen Immunsystems bei akuten und chronischen Lebererkrankungen. Wiener klinische Wochenschrift 121:23-24, 732-744
CrossRef10
M. Márquez, C. Fernández-Gutiérrez, M. Montes-de-Oca, M. J. Blanco, F. Brun, C. Rodríguez-Ramos, J. A. Girón-González. (2009) Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis. Clinical & Experimental Immunology 158:2, 219-229
CrossRef11
B. Massonnet, A. Delwail, J.-M. Ayrault, C. Chagneau-Derrode, J.-C. Lecron, C. Silvain. (2009) Increased immunoglobulin A in alcoholic liver cirrhosis: exploring the response of B cells to Toll-like receptor 9 activation. Clinical & Experimental Immunology 158:1, 115-124
CrossRef12
Hermann Neugebauer, Pia Hartmann, Sebastian Krenn, Thomas Glück, Jürgen Schölmerich, Rainer Straub, Reiner Wiest. (2008) Bacterial translocation increases phagocytic activity of polymorphonuclear leucocytes in portal hypertension: priming independent of liver cirrhosis. Liver International 28:8, 1149-1157
CrossRef13
A. Amorós, J. Such. (2008) Infección bacteriana en la cirrosis hepática. Medicine - Programa de Formación Médica Continuada Acreditado 10:11, 720-725
CrossRef14
Anne B. Lipke, Anastasios A. Mihas. (2007) Non-decompensated Cirrhosis as a Risk Factor for Invasive Aspergillosis: A Case Report and Review of the Immune Dysfunction of Cirrhosis. The American Journal of the Medical Sciences 334:4, 314-316
CrossRef15
Leonidas Christou, Georgios Pappas, Matthew E. Falagas. (2007) Bacterial Infection-Related Morbidity and Mortality in Cirrhosis. The American Journal of Gastroenterology 102:7, 1510-1517
CrossRef16
Rosario González Alonso, Mónica González García, Agustín Albillos Martínez. (2007) Fisiopatología de la translocación y la peritonitis bacteriana espontánea en la cirrosis. Gastroenterología y Hepatología 30:2, 78-84
CrossRef17
Sahar Ghassemi, Guadalupe Garcia-Tsao. (2007) Prevention and treatment of infections in patients with cirrhosis. Best Practice & Research Clinical Gastroenterology 21:1, 77-93
CrossRef18
John C.M. Brust. 2007. Éthanol. , 385-516.
CrossRef19
Frédéric Bert, Claire Bellier, Ludovic Lassel, Valérie Lefranc, François Durand, Jacques Belghiti, France Mentré, Bruno Fantin. (2005) Risk factors forStaphylococcus aureus infection in liver transplant recipients. Liver Transplantation 11:9, 1093-1099
CrossRef20
Reiner Wiest, Guadalupe Garcia-Tsao. (2005) Bacterial translocation (BT) in cirrhosis. Hepatology 41:3, 422-433
CrossRef21
EDWARD GANE. (2004) Renal transplantation in chronic hepatitis C. Journal of Gastroenterology and Hepatology 19:s7, S99-S102
CrossRef22
F. Fabrizi, P. Martin, V. Dixit, S. Bunnapradist, G. Dulai. (2004) Meta-analysis: effect of hepatitis C virus infection on mortality in dialysis. Alimentary Pharmacology and Therapeutics 20:11-12, 1271-1277
CrossRef23
Raymond K. Cross, Charles Howell. (2003) Two Cases of Spontaneous Epidural Abscess in Patients with Cirrhosis. Southern Medical Journal 96:3, 291-293
CrossRef24
Edward Gane, Helen Pilmore. (2002) Management of chronic viral hepatitis before and after renal transplantation. Transplantation 74:4, 427-437
CrossRef25
Ricard Solà, Germán Soriano. (2002) Why do bacteria reach ascitic fluid?. European Journal of Gastroenterology & Hepatology 14:4, 351-354
CrossRef26
Georg Engelich, Daniel G. Wright, Kevan L. Hartshorn. (2001) Acquired Disorders of Phagocyte Function Complicating Medical and Surgical Illnesses. Clinical Infectious Diseases 33:12, 2040-2048
CrossRef27
Javier Fernández, Tilman M. Bauer, Miquel Navasa, Juan Rodés. (2000) Diagnosis, treatment and prevention of spontaneous bacterial peritonitis. Best Practice & Research Clinical Gastroenterology 14:6, 975-990
CrossRef28
Atsushi Moriyama, Akinari Tabaru, Hideaki Unoki, Shintaro Abe, Akihide Masumoto, Makoto Otsuki. (2000) Plasma nitrite/nitrate concentrations as a tumor marker for hepatocellular carcinoma. Clinica Chimica Acta 296:1-2, 181-191
CrossRef29
Heitor Rosa, Americo O. Silverio, Rafael F. Perini, Claudia B. Arruda. (2000) Bacterial infection in cirrhotic patients and its relationship with alcohol. The American Journal of Gastroenterology 95:5, 1290-1293
CrossRef30
Brigitte Vollmar, S
ren Siegmund, Sven Richter, Michael D. Menger. (1999) Microvascular consequences of Kupffer cell modulation in rat liver fibrogenesis. The Journal of Pathology 189:1, 85-91
CrossRef31
Shanop Shuangshoti Shuangshoti, Samruay Shuangshoti. (1999) Tuberculous brain abscess: A case report with a review of the literature in English. Neuropathology 19:3, 328-335
CrossRef32
Stefan Worgall, Petr Bezdicek, Moo-Kyung Kim, Jong-Gu Park, Ravi Singh, Melpo Christofidou-Solomidou, Alice Prince, Imre Kovesdi, Alan D. Schreiber, Ronald G. Crystal. (1999) Augmentation of pulmonary host defense against Pseudomonas by FcγRIIA cDNA transfer to the respiratory epithelium. Journal of Clinical Investigation 104:4, 409-418
CrossRef33
F. L. Iber. (1999) Patients With Cirrhosis and Liver Failure Are at Risk for Bacterial and Fungus Infection. The American Journal of Gastroenterology 94:8, 2001-2003
CrossRef34
F. Gomez, P. Ruiz, F. Briceño, C. Rivera, R. Lopez. (1999) Macrophage Fcγ Receptors Expression Is Altered by Treatment with Dopaminergic Drugs. Clinical Immunology 90:3, 375-387
CrossRef35
Sho-Ichiro Hagiwara, Motohiro Takeya, Hiroshi Suzuki, Tatsuhiko Kodama, Luc J.W. van der Laan, Georg Kraal, Nobuo Kitamura, Kiyoshi Takahashi. (1999) Role of Macrophage Scavenger Receptors in Hepatic Granuloma Formation in Mice. The American Journal of Pathology 154:3, 705-720
CrossRef36
Xiao-Qing Pan, Christine Darby, Zena K. Indik, Alan D. Schreiber. (1999) Activation of Three Classes of Nonreceptor Tyrosine Kinases Following Fcγ Receptor Crosslinking in Human Monocytes. Clinical Immunology 90:1, 55-64
CrossRef37
Brian J.G. Pereira, Svetlozar N. Natov, Beth A. Bouthot, B. V. R. Murthy, Robin Ruthazer, Christopher H. Schmid, Andrew S. Levey, . (1998) Effect of hepatitis C infection and renal transplantation on survival in end-stage renal disease1. Kidney International 53:5, 1374-1381
CrossRef38
Moura, Verheul, Marx. (1998) A functional defect in hereditary haemochromatosis monocytes and monocyte-derived macrophages. European Journal of Clinical Investigation 28:2, 164-173
CrossRef39
Ingmar A. F. M. Heijnen, Jan G. J. Van de Winkel. (1997) Human IgG Fc Receptors. International Reviews of Immunology 16:1-2, 29-55
CrossRef40
Harvey E. Finkel. (1996) Wine and health: a review and perspective. Journal of Wine Research 7:3, 157-196
CrossRef41
Jaime Pereira, Luigi Accatino, Jorge Alfaro, Javier Brahm, Patricia Hidalgo, Diego Mezzano. (1995) Platelet autoantibodies in patients with chronic liver disease. American Journal of Hematology 50:3, 173-178
CrossRef42
Carlos Guarner, Bruch A. Runyon. (1995) Macrophage function in cirrhosis and the risk of bacterial infection. Hepatology 22:1, 367-369
CrossRef43
JEAN-JACQUES MONTSENY, ALAIN MEYRIER, DIETER KLEINKNECHT. (1995) The Current Spectrum of Infectious Glomerulonephritis. Medicine 74:2, 63-73
CrossRef44
Herbert Y. Reynolds. (1995) Pulmonary Host Defenses. Alcoholism: Clinical and Experimental Research 19:1, 6-10
CrossRef
